INFLAMMATION AIRWAYS REACTIVITY AND ASTHMA

该计划的主要目标是（1）解决免疫学 哮喘受试者中存在的异常， 反应发展在他们的气道，（2）探索机制，通过 哪些炎症细胞改变气道反应性，以及（3）确定 炎症反应对气道上皮细胞的影响， 神经组织 中心假设是免疫系统的异常 以T细胞为中心的调节存在于哮喘受试者中， 这些T细胞异常协调了许多 与哮喘相关的特征。 当气道炎症发生时， 来自一系列炎症细胞的阳离子蛋白质在 气道反应性的改变。 此外，炎症 通过增加乙酰胆碱的释放来改变气道的神经控制， 导致气道反应性增强的交界前部位。 研究 将在人类和动物模型中进行， 一组代表多个学科的调查人员， 肺生理学和免疫学以及分子生物学技术 和细胞生物学。 在临床研究中，T细胞的性质和调节 细胞识别哮喘患者气道中的变应原表位将 接受检查。 作为这些研究的一部分， 明确定义的过敏原可被T细胞识别，但不被结合的IgE识别 效应细胞将在其治疗中的作用方面进行检查， 疾病 将研究类固醇抵抗的哮喘受试者， 确定是否有持续的免疫激活和炎症内 类固醇治疗后的气道。 生物化学和分子 将在新鲜分离的 来自这些患者的外周血单核细胞和T细胞系。 在夜间哮喘受试者中，他们有异常哮喘的假设 控制免疫反应以及改变气道的神经控制 将被研究。 动物模型的研究将扩展问题 进入人类不容易研究的领域。 当在没有明显气道的情况下观察到气道高反应性时 将在C5片段诱导的兔模型中研究炎症 鼻窦炎与气溶胶致敏小鼠模型 暴露于抗原。 在小鼠系统中， 过敏原特异性和多克隆IgE对气道发育 将评估高反应性。 阳离子蛋白质的能力， 单独或与脂质结合时， 将在家兔和大鼠中讨论介质， 负责增强神经和胆碱能介导的反应 将在抗原激发的兔和小鼠中进行研究。 这些 调查应深入了解 免疫调节的异常改变气道细胞的功能， 导致气道反应性增加。

The primary objectives of this program are to (1) address the immunologic abnormalities present in subjects with asthma that allow inflammatory reactions to develop within their airways, (2) probe the mechanisms through which inflammatory cells alter airways responsiveness, and (3) define the consequences of inflammatory reactions on airway epithelial cells and neural tissue. The central hypotheses are that abnormalities in immune regulation centered around T cells are present in subjects with asthma, and that these T cell abnormalities orchestrate many of the immunopathogenic features associated with asthma. When airways inflammation occurs, cationic proteins from an array of inflammatory cells play a critical role in the alteration of airways responsiveness. In addition, inflammation alters neural control of airways by enhancing release of acetylcholine at prejunctional sites leading to enhanced airways responsiveness. Studies that address these hypotheses will be conducted in man and animal models by a group of investigators representing multiple disciplines and employing the techniques of pulmonary physiology and immunology as well as molecular and cellular biology. In clinical studies, the nature and regulation of T cell recognition of allergenic epitopes in the airways of asthmatics will be examined. As part of these studies, the ability to utilize a fragment of well defined allergen recognized by T cells but not by IgE bound to effector cells will be examined in terms of its role in the therapy of disease. Steroid resistant subjects with asthma will be studied to determine if there is persistent immune activation and inflammation within their airways following steroid therapy. The biochemical and molecular basis for steroid resistance will be examined in freshly isolated peripheral blood mononuclear cells and T cell lines from these patients. In subjects with nocturnal asthma, the hypotheses that they have abnormal control of immune responses as well as altered neural control of airways will be studied. Investigations in animal models will extend questions into areas not easily examined in man. The mechanisms that are operative when airways hyperresponsiveness is seen in the absence of overt airways inflammation will be studied in a rabbit model of C5 fragment-induced sinusitis and a murine model of antigen sensitization induced by aerosol exposure to antigen. Within the murine system, the contribution of allergen-specific and polyclonal IgE to the development of airways hyperresponsiveness will be assessed. The ability of cationic proteins to produce increases in responsiveness alone and when combined with lipid mediators will be addressed in rabbits and rats while mechanisms responsible for enhanced neural and cholinergically mediated responsiveness will be studied in antigen-challenged rabbits and mice. These investigations should provide insight into the mechanisms through which abnormalities of immune regulation alter the function of airway cells and tissues leading to increased airways responsiveness.